We have demonstrated that the signal(s) transmitted upon occupancy of the antigen-specific receptor inhibit the growth of transformed T cells. This observation has been extended by using monoclonal antibodies to activate T cells. Within 24 hours of exposure to stimulatory antibodies directed against CD3 (mouse and human T cells) or Thy-1 (mouse T cells), transformed T cells secreted interleukin 2 and ceased their spontaneous proliferation. The specificity of this effect was ascertained in several ways: (1) external crosslinking of the anti-CD3 antibodies, either by Fc receptor-bearing accessory cells or by adherence to plastic, was required for growth to be inhibited, and (2) non-stimulatory anti- Thy-1 antibodies blocked the action of the stimulatory antibodies, i.e., allowed the transformed T cells to grow normally. The cell cycle block in T cell hybridomas, but not a chemically-induced transformed T cell, was followed by death, as evidenced by the release of 52-Cr or LDH. Cell cycle analysis demonstrated that the activated cells developed a block between the G1 and S phases, and the transit of cells in S phase was slowed. Furthermore, the chemically-induced T cell tumor, but not the T cell hybridoma, appeared to be able to assume a GO-like state, perhaps explaining its failure to rapidly lyse in response to activation. The in vivo growth of antigen-specific T cell hybridomas has been studied in a mouse tumor model. Introduction of the tumor (subcutaneously) and of the appropriate stimulatory antigen (intraperitoneally) resulted in complete rejection of the neoplasm. Even when treatment was not initiated until the tumor was well established, injection of antigen caused the tumor at the primary site of injection to regress in virtually all cases, resulted in long-term survival in over one-third of the animals. Studies using stimulatory monoclonal anti-CD3 or anti- Thy-1 antibodies in this tumor model system are planned.